The addition of bevacizumab to osimertinib failed to prolong progression-free survival (PFS) compared with osimertinib alone in patients with previously treated EGFR T790M-mutant non-small cell lung cancer (NSCLC), according to the results of a phase 2 study published in JAMA Oncology.1
Although osimertinib is known to better prolong PFS than cytotoxic chemotherapy in patients with EGFR-mutated NSCLC, the median time to progression is 10 to 13 months. The investigators hypothesized that the addition of an anti-VEGF agent to osimertinib would lead to synergy based on activity seen in preclinical models.
The 8715L trial (UMIN Clinical Trials Registry Identifier: UMIN000023761) included 87 patients in Japan, 6 of whom were part of a safety lead-in. There were 81 patients in the phase 2 portion who were randomly assigned to receive bevacizumab plus osimertinib or osimertinib alone. The primary end point was PFS and the secondary end points included overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), and safety.
In the phase 2 portion, the baseline median age was 70 years and 68 years in the osimertinib monotherapy and combination arms respectively. Forty-one percent of the patients who received single-agent osimertinib were male; this number was 40% in the doublet therapy group. In the control arm, most patients were current or former smokers (51%); in the experimental arm, 48% of patients had a smoking history.
The majority of patients had stage IV disease and all had received a prior EGFR tyrosine kinase inhibitor. All patients also had the EGFR T790M mutation, and most also had an exon 19 deletion (monotherapy arm, 68%; combination arm, 55%). Thirty-two percent and 45% of patients in the control and experimental groups had an exon 21 L858R mutation, respectively.
Although the combination of bevacizumab and osimertinib led to an ORR of 71.8% vs 55.0% with osimertinib alone, this did not translate to an improvement in PFS. The median PFS was 9.4 months with the combination compared with 13.5 months with osimertinib alone (adjusted HR, 1.44; 80% CI, 1.00-2.08; P =.20).
Subset analyses did not identify a group in which the combination demonstrated a PFS benefit. TTF was 8.4 months and 11.2 months in the combination and osimertinib arms, respectively (adjusted HR, 1.54; 95% CI, 0.90-2.69; P =.12).
OS was also similar between arms. In the combination group, the median OS was not reached compared with 22.1 months in the osimertinib group (adjusted HR, 1.02; 95% CI, 0.43-2.44; P =.96).
Bevacizumab plus osimertinib was well-tolerated, with most adverse events (AEs) classified as grade 1 or 2. The AEs that occurred more frequently with the combination vs single-agent osimertinib were proteinuria and hypertension. Hematologic and dermatologic AEs were similar between the arms, and there were no cases of serious bleeding or embolism with bevacizumab.
“Although ORR was slightly better in the combination arm, we could not show advantages in PFS and OS,” the investigators concluded. However, they cautioned that “this single study may not be conclusive” due to the “small number of patients,” which constituted a study limitation.
Disclosures: Some of the study authors disclosed financial relationships with the pharmaceutical industry and/or the medical device industry. For a full list of disclosures, please refer to the original study.
Akamatsu H, Toi Y, Hayashi H, et al. Efficacy of osimertinib plus bevacizumab vs osimertinib in patients with EGFR T790M–mutated non–small cell lung cancer previously treated with epidermal growth factor receptor–tyrosine kinase inhibitor: West Japan Oncology Group 8715L phase 2 randomized clinical trial. JAMA Oncol. Published online January 7, 2021. doi:10.1001/jamaoncol.2020.6758